PROJECT SUMMARY/ABSTRACT ? Neuropathology Core The overarching goal of the UCD ADC is to understand the multiple and complex determinants that explain heterogeneity of cognitive trajectories in diverse older adults. To help achieve this goal, the primary mission of our Neuropathology Core (NPC) has been to assess brain injury in the form of multiple pathologies, which provides an essential set of data that is perhaps the most precise and most relevant to an individual's cognitive abilities. In addition to providing neuropathologic diagnosis, the NPC also collects and stores brain tissue, serum, plasma, and DNA/RNA samples from subjects with mild cognitive impairment (MCI), AD, other neurodegenerative disorders, as well as healthy controls. Equipped with our neuropathological expertise, data, technologies, and biological samples from a heterogeneous cohort of dementia, MCI and cognitively normal subjects, the NPC is instrumental in fostering comprehensive and in-depth research to identify modifiers of cognitive trajectories and biomarkers with predictive value, and in providing education to professionals, trainees, and the general public about dementia. Over the last five years, the NPC has transformed from a traditional diagnostic unit to fully integrated participation in multiple research projects. In this renewal application, the NPC will continue to perform its core functions, support existing collaborations, cultivate new junior scientists, and seek new opportunities building on the progress achieved during the current grant cycle. Our specific aims are: Aim 1. Provide neuropathological diagnoses for all longitudinal cohort participants using standardized criteria, and examine clinicopathological correlations. The NPC has placed emphasis on identifying mixed pathologies including cerebrovascular injuries, reflecting the protective/risk factors of brain aging and dementia processes in our diverse, multi-ethnic longitudinal cohort. Aim 2. Maintain a state-of-the-art biorepository of brain tissue, blood, and DNA/RNA to provide ADC projects, collaborative projects, and qualified investigators with high quality, well-characterized samples, neuropathological data, and neuropathological services. Aim 3. Participate in and facilitate dementia-related basic and translational projects using NPC resources. Currently three major interrelated themes have emerged: (1) microglia pathology and neuroinflammation; (2) vascular and white matter injury; and (3) multi-ethnic diversity and biomarkers. Aim 4. Interact with other ADC Cores to provide neuropathological education to medical staff, researchers, trainees/students, and the general public, and to cultivate junior scientists. In summary, these studies conducted by the NPC will help refine neuropathologic diagnosis, enable precise detection of diverse brain injury pathways, identify biomarkers with value in predicting cognitive decline, and contribute to the effort to find new avenues for dementia treatment.